Skip to main content

Advertisement

SpringerLink
Log in

Noninvasive prenatal testing: from aneuploidy to single genes

  • Review
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Noninvasive prenatal testing has undergone rapid advances in the last few years. Although researchers have long known about circulating pregnancy-based cell-free fragments of DNA in maternal plasma, it was the introduction of massively parallel sequencing that allowed noninvasive prenatal testing to become a widely used clinical test. This review will begin with an in-depth analysis of the use of noninvasive prenatal testing for aneuploidy, including common causes for inaccurate and/or discordant results. It will also review the ongoing expansion of noninvasive prenatal testing to include copy number variants and select single-gene disorders. Finally, integrated throughout the review is a comparison of noninvasive prenatal testing to more traditional screening methods along with some medical and ethical implications of the widespread use of this new technology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Akolekar R, Beta J, Picciarelli G, Ogilvie C, D’Antonio F (2015) Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 45:16–26

    Article  CAS  Google Scholar 

  • Ashoor G, Syngelaki A, Poon LC, Rezende JC, Nicolaides KH (2013) Fetal fraction in maternal plasma cell-free DNA at 11-13 weeks’ gestation: relation to maternal and fetal characteristics. Ultrasound Obstet Gynecol 41(1):26–32. https://doi.org/10.1002/uog.12331(Epub 2012 Dec 4)

    Article  CAS  PubMed  Google Scholar 

  • Bevilacqua E, Gil MM, Nicolaides KH, Ordoñez E, Cirigliano V, Dierickx H, Willems PJ, Jani JC (2015) Performance of screening for aneuploidies by cell-free DNA analysis of maternal blood in twin pregnancies. Ultrasound Obstet Gynecol 45(1):61–66. https://doi.org/10.1002/uog.14690(Epub 2014 Dec 4)

    Article  CAS  PubMed  Google Scholar 

  • Bianchi DW (2018) Cherchez la femme: maternal incidental findings can explain discordant prenatal cell-free DNA sequencing results. Genet Med. 20(9):910–917. https://doi.org/10.1038/gim.2017.219(Epub 2017 Dec 7. Review)

    Article  CAS  PubMed  Google Scholar 

  • Bianchi DW, Chiu RWK (2018) Sequencing of circulating cell-free DNA during pregnancy. N Engl J Med 379(5):464–473. https://doi.org/10.1056/nejmra1705345(Review. PubMed PMID: 30067923)

    Article  CAS  PubMed  Google Scholar 

  • Bianchi DW, Rava RP, Sehnert AJ (2014) DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 371(6):578. https://doi.org/10.1056/nejmc1405486

    Article  CAS  PubMed  Google Scholar 

  • Bianchi DW, Chudova D, Sehnert AJ, Bhatt S, Murray K, Prosen TL, Garber JE, Wilkins-Haug L, Vora NL, Warsof S, Goldberg J, Ziainia T, Halks-Miller M (2015) Noninvasive prenatal testing and incidental detection of occult maternal malignancies. JAMA 314(2):162–169. https://doi.org/10.1001/jama.2015.7120

    Article  CAS  PubMed  Google Scholar 

  • Brison N, Van Den Bogaert K, Dehaspe L, van den Oever JM, Janssens K, Blaumeiser B, Peeters H, Van Esch H, Van Buggenhout G, Vogels A, de Ravel T, Legius E, Devriendt K, Vermeesch JR (2017) Accuracy and clinical value of maternal incidental findings during noninvasive prenatal testing for fetal aneuploidies. Genet Med. 19(3):306–313. https://doi.org/10.1038/gim.2016.113(Epub 2016 Sep 1)

    Article  CAS  PubMed  Google Scholar 

  • Bunnell M, Zhang C, Lee C et al (2017) Confined placental mosaicism for 22q11.2 deletion as the etiology for discordant positive NIPT results. Prenat Diag. 37:416–419

    Article  CAS  Google Scholar 

  • Canick JA, Kloza EM, Lambert-Messerlian GM, Haddow JE, Ehrich M, van den Boom D, Bombard AT, Deciu C, Palomaki GE (2012) DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations. Prenat Diagn. 32(8):730–734. https://doi.org/10.1002/pd.3892(Epub 2012 May 14)

    Article  CAS  PubMed  Google Scholar 

  • Carlson LM, Hardisty E, Coombs CC, Vora NL (2018) Maternal malignancy evaluation after discordant cell-free DNA results. Obstet Gynecol 131(3):464–468. https://doi.org/10.1097/aog.0000000000002474

    Article  PubMed  PubMed Central  Google Scholar 

  • Carlson LM, Harris S, Hardisty EE, Hocutt G, Vargo D, Campbell E, Davis E, Gilmore K, Vora NL (2019) Use of a novel computerized decision aid for aneuploidy screening: a randomized controlled trial. Genet Med. 21(4):923–929. https://doi.org/10.1038/s41436-018-0283-2(Epub 2018 Sep 14)

    Article  PubMed  Google Scholar 

  • Chitty LS, Griffin DR, Meaney C, Barrett A, Khalil A, Pajkrt E, Cole TJ (2011) New aids for the non-invasive prenatal diagnosis of achondroplasia: dysmorphic features, charts of fetal size and molecular confirmation using cell-free fetal DNA in maternal plasma. Ultrasound Obstet Gynecol 37(3):283–289. https://doi.org/10.1002/uog.8893

    Article  CAS  PubMed  Google Scholar 

  • Chitty LS, Khalil A, Barrett AN, Pajkrt E, Griffin DR, Cole TJ (2013) Safe, accurate, prenatal diagnosis of thanatophoric dysplasia using ultrasound and free fetal DNA. Prenat Diagn 33(5):416–423. https://doi.org/10.1002/pd.4066

    Article  CAS  PubMed  Google Scholar 

  • Chitty LS, Finning K, Wade A, Soothill P, Martin B, Oxenford K, Daniels G, Massey E (2014) Diagnostic accuracy of routine antenatal determination of fetal RHD status across gestation: population based cohort study. BMJ 349:g5243. https://doi.org/10.1136/bmj.g5243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Committee on Practice Bulletins-Obstetrics, Committee on Genetics, Society for Maternal-Fetal Medicine (2016) Practice bulletin no. 163: screening for fetal aneuploidy. Obstet Gynecol 127(5):123–137

    Article  Google Scholar 

  • Curnow KJ, Wilkins-Haug L, Ryan A, Kırkızlar E, Stosic M, Hall MP, Sigurjonsson S, Demko Z, Rabinowitz M, Gross SJ (2015) Detection of triploid, molar, and vanishing twin pregnancies by a single-nucleotide polymorphism-based noninvasive prenatal test. Am J Obstet Gynecol 212(1):79.e1–79.e9. https://doi.org/10.1016/j.ajog.2014.10.012

    Article  CAS  Google Scholar 

  • Dar P, Curnow KJ, Gross SJ, Hall MP, Stosic M, Demko Z, Zimmermann B, Hill M, Sigurjonsson S, Ryan A, Banjevic M, Kolacki PL, Koch SW, Strom CM, Rabinowitz M, Benn P (2014) Clinical experience and follow-up with large scale single-nucleotide polymorphism-based noninvasive prenatal aneuploidy testing. Am J Obstet Gynecol 211(5):527.e1–527.e17. https://doi.org/10.1016/j.ajog.2014.08.006

    Article  Google Scholar 

  • Dar P, Shani H, Evans MI (2016) Cell-free DNA: comparison of technologies. Clin Lab Med. 36(2):199–211. https://doi.org/10.1016/j.cll.2016.01.015(Epub 2016 Mar 18. Review)

    Article  PubMed  Google Scholar 

  • Deans Z, Hill M, Chitty LS, Lewis C (2013) Non-invasive prenatal testing for single gene disorders: exploring the ethics. Eur J Hum Genet. 21(7):713–718. https://doi.org/10.1038/ejhg.2012.250(Epub 2012 Nov 28)

    Article  PubMed  Google Scholar 

  • del Mar Gil M, Quezada MS, Bregant B, Syngelaki A, Nicolaides KH (2014) Cell-free DNA analysis for trisomy risk assessment in first-trimester twin pregnancies. Fetal Diagn Ther 35(3):204–211. https://doi.org/10.1159/000356495(Epub 2013 Nov 15)

    Article  Google Scholar 

  • Fan C et al (2008) Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc Natl Acad Sci 105(42):16266–16271

    Article  CAS  Google Scholar 

  • Futch T, Spinosa J, Bhatt S, de Feo E, Rava RP, Sehnert AJ (2013) Initial clinical laboratory experience in noninvasive prenatal testing for fetal aneuploidy from maternal plasma DNA samples. Prenat Diagn 33(6):569–574. https://doi.org/10.1002/pd.4123

    Article  PubMed  PubMed Central  Google Scholar 

  • Galeva S, Konstantinidou L, Gil MM, Akolekar R, Nicolaides KH (2018) Routine first-trimester screening for fetal trisomies in twin pregnancy: cell-free DNA test contingent on results from combined test. Ultrasound Obstet Gynecol. https://doi.org/10.1002/uog.20160(Epub ahead of print)

    Article  PubMed  Google Scholar 

  • Gil MM, Accurti V, Santacruz B, Plana MN, Nicolaides KH (2017) Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 50(3):302–314. https://doi.org/10.1002/uog.17484(Epub 2017 Jul 27. Review)

    Article  CAS  PubMed  Google Scholar 

  • Grace MR, Hardisty E, Green NS, Davidson E, Stuebe AM, Vora NL (2015) Cell free DNA testing-interpretation of results using an online calculator. Am J Obstet Gynecol 213(1):30.e1–30.e4. https://doi.org/10.1016/j.ajog.2015.05.004(Epub 2015 May 5)

    Article  Google Scholar 

  • Grati FR, Bajaj K, Malvestiti F, Agrati C, Grimi B, Malvestiti B, Pompilii E, Maggi F, Gross S, Simoni G, Ferreira JC (2015) The type of feto-placental aneuploidy detected by cfDNA testing may influence the choice of confirmatory diagnostic procedure. Prenat Diagn 35(10):994–998. https://doi.org/10.1002/pd.4659(Epub 2015 Sep 11)

    Article  CAS  PubMed  Google Scholar 

  • Haghiac M, Vora NL, Basu S, Johnson KL, Presley L, Bianchi DW, Hauguel-de Mouzon S (2012) Increased death of adipose cells, a path to release cell-free DNA into systemic circulation of obese women. Obesity (Silver Spring). 20(11):2213–2219. https://doi.org/10.1038/oby.2012.138(Epub 2012 Jun 7. Erratum in: Obesity (Silver Spring). 2012;20(11):2321)

    Article  CAS  PubMed Central  Google Scholar 

  • Han CS, Platt LD (2014) Noninvasive prenatal testing: need for informed enthusiasm. Am J Obstet Gynecol 211(6):577–580. https://doi.org/10.1016/j.ajog.2014.09.012(Epub 2014 Nov 25)

    Article  PubMed  Google Scholar 

  • Helgeson J, Wardrop J, Boomer T et al (2015) Clinical outcome of subchromosomal event detected by whole-genome noninvasive prenatal testing. Prenat Diagn 35:999–1004

    Article  CAS  Google Scholar 

  • Iwarsson E, Jacobsson B, Dagerhamn J, Davidson T, Bernabé E, Heibert Arnlind M (2017) Analysis of cell-free fetal DNA in maternal blood for detection of trisomy 21, 18 and 13 in a general pregnant population and in a high risk population—a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 96(1):7–18. https://doi.org/10.1111/aogs.13047(Epub 2016 Dec 9. Review)

    Article  CAS  PubMed  Google Scholar 

  • Jain CV, Kadam L, van Dijk M, Kohan-Ghadr HR, Kilburn BA, Hartman C, Mazzorana V, Visser A, Hertz M, Bolnick AD, Fritz R, Armant DR, Drewlo S (2016) Fetal genome profiling at 5 weeks of gestation after noninvasive isolation of trophoblast cells from the endocervical canal. Sci Transl Med 8(363):363re4

    Article  Google Scholar 

  • Jenkins LA, Deans ZC, Lewis C, Allen S (2018) Delivering an accredited non-invasive prenatal diagnosis service for monogenic disorders and recommendations for best practice. Prenat Diagn 38(1):44–51. https://doi.org/10.1002/pd.5197

    Article  PubMed  Google Scholar 

  • Jensen T, Dzakula Z, Deciu C et al (2012) Detection of microdeletion 22q11.2 in a fetus by next-generation sequencing of maternal plasma. Clin Chem 58(7):1148–1151

    Article  CAS  Google Scholar 

  • Lapaire O, Holzgreve W, Oosterwijk JC, Brinkhaus R, Bianchi DW (2007) Georg Schmorl on trophoblasts in the maternal circulation. Placenta 28(1):1–5

    Article  CAS  Google Scholar 

  • Larion S, Warsof SL, Romary L, Mlynarczyk M, Peleg D, Abuhamad AZ (2014) Uptake of noninvasive prenatal testing at a large academic referral center. Am J Obstet Gynecol 211:651.e1–651.e7

    Article  Google Scholar 

  • Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW, Wainscoat JS (1997) Presence of fetal DNA in maternal plasma and serum. Lancet 350(9076):485–487

    Article  CAS  Google Scholar 

  • Le Conte G, Letourneau A, Jani J, Kleinfinger P, Lohmann L, Costa JM, Benachi A (2018) Cell-free fetal DNA analysis in maternal plasma as screening test for trisomies 21, 18 and 13 in twin pregnancy. Ultrasound Obstet Gynecol 52(3):318–324. https://doi.org/10.1002/uog.18838

    Article  PubMed  Google Scholar 

  • Mulla BM, Chang OH, Modest AM, Hacker MR, Marchand KF, O’Brien KE (2018) Improving patient knowledge of aneuploidy testing using an educational video: a randomized controlled trial. Obstet Gynecol 132(2):445–452. https://doi.org/10.1097/aog.0000000000002742

    Article  PubMed  PubMed Central  Google Scholar 

  • National Society of Genetic Counselors (2019) NIPT/cell free DNA screening predictive value calculator. https://www.perinatalquality.org/Vendors/NSGC/NIPT/. Accessed 27 Jan 2019

  • Nicolaides KH, Syngelaki A, del Mar Gil M, Quezada MS, Zinevich Y (2014) Prenatal detection of fetal triploidy from cell-free DNA testing in maternal blood. Fetal Diagn Ther 35(3):212–217. https://doi.org/10.1159/000355655(Epub 2013 Oct 10)

    Article  PubMed  Google Scholar 

  • Norton ME, Wapner RJ (2015) Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med 373(26):2582. https://doi.org/10.1056/nejmc1509344

    Article  PubMed  Google Scholar 

  • Norton ME, Biggio JR, Kuller JA, Blackwell SC (2017) The role of ultrasound in women who undergo cell-free DNA screening. Am J Obstet Gynecol. 216(3):B2–B7. https://doi.org/10.1016/j.ajog.2017.01.005(Epub 2017 Jan 17)

    Article  PubMed  Google Scholar 

  • Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, van den Boom D, Bombard AT, Deciu C, Grody WW, Nelson SF, Canick JA (2011) DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med. 13(11):913–920. https://doi.org/10.1097/gim.0b013e3182368a0e

    Article  CAS  PubMed  Google Scholar 

  • Rubeis G, Steger F (2018) A burden from birth? Non-invasive prenatal testing and the stigmatization of people with disabilities. Bioethics. https://doi.org/10.1111/bioe.12518(Epub ahead of print)

    Article  PubMed  Google Scholar 

  • Schmorl G (1983) Pathologisch-anatomische Untersuchungen über Puerperal-Eklampsie. Verlag FCW Vogel, Leipzig

  • Snyder MW, Simmons LE, Kitzman JO, Coe BP, Henson JM, Daza RM, Eichler EE, Shendure J, Gammill HS (2015) Copy-number variation and false positive prenatal aneuploidy screening results. N Engl J Med. 372(17):1639–1645. https://doi.org/10.1056/nejmoa1408408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Srinivasan A, Bianchi DW, Huang H, Sehnert AJ, Rava RP (2013) Noninvasive detection of fetal subchromosome abnormalities via deep sequencing of maternal plasma. Am J Hum Genet 92(2):167–176. https://doi.org/10.1016/j.ajhg.2012.12.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tamminga S, van Maarle M, Henneman L, Oudejans CB, Cornel MC, Sistermans EA (2016) Maternal plasma DNA and RNA sequencing for prenatal testing. Adv Clin Chem. 74:63–102. https://doi.org/10.1016/bs.acc.2015.12.004(Epub 2016 Jan 21. Review)

    Article  CAS  PubMed  Google Scholar 

  • Taylor TH, Gitlin SA, Patrick JL, Crain JL, Wilson JM, Griffin DK (2014) The origin, mechanisms, incidence and clinical consequences of chromosomal mosaicism in humans. Hum Reprod Update 20(4):571–581. https://doi.org/10.1093/humupd/dmu016(Epub 2014 Mar 25. Review)

    Article  CAS  PubMed  Google Scholar 

  • Taylor-Phillips S, Freeman K, Geppert J, Agbebiyi A, Uthman OA, Madan J, Clarke A, Quenby S, Clarke A (2016) Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes: a systematic review and meta-analysis. BMJ Open 6(1):e010002. https://doi.org/10.1136/bmjopen-2015-010002(Review)

    Article  PubMed  PubMed Central  Google Scholar 

  • Vora N, O’Brien B (2014) Noninvasive prenatal testing for microdeletion syndromes and expanded trisomies. Obstet Gynecol 123(5):1097–1099

    Article  Google Scholar 

  • Walknowska J, Conte FA, Grumbach MM (1969) Practical and theoretical implications of fetal-maternal lymphocyte transfer. Lancet 1(7606):1119–1122

    Article  CAS  Google Scholar 

  • Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, Savage M, Platt LD, Saltzman D, Grobman WA, Klugman S, Scholl T, Simpson JL, McCall K, Aggarwal VS, Bunke B, Nahum O, Patel A, Lamb AN, Thom EA, Beaudet AL, Ledbetter DH, Shaffer LG, Jackson L (2012) Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 367(23):2175–2184. https://doi.org/10.1056/nejmoa1203382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang J, Ding X, Zhu W (2018) Improving the calling of non-invasive prenatal testing on 13-/18-/21-trisomy by support vector machine discrimination. PLoS One. 13(12):0207840. https://doi.org/10.1371/journal.pone.0207840(eCollection 2018)

    Article  Google Scholar 

  • Yatsenko S, Peters D, Saller D et al (2014) Maternal cell-free DNA-based screening for fetal microdeletion and the importance of careful diagnostic follow-up. Genet Med. 17(10):836–838

    Article  Google Scholar 

  • Zhang J, Li J, Saucier JB, Feng Y, Jiang Y, Sinson J, McCombs AK, Schmitt ES, Peacock S, Chen S, Dai H, Ge X, Wang G, Shaw CA, Mei H, Breman A, Xia F, Yang Y, Purgason A, Pourpak A, Chen Z, Wang X, Wang Y, Kulkarni S, Choy KW, Wapner RJ, Van den Veyver IB, Beaudet A, Parmar S, Wong LJ, Eng CM (2019) Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA. Nat Med 25(3):439–447. https://doi.org/10.1038/s41591-018-0334-x(Epub 2019 Jan 28. Erratum in: Nat Med. 2019 Feb 20)

    Article  CAS  PubMed  Google Scholar 

  • Zhao C, Tynan J, Ehrich M et al (2015) Detection of fetal subchromosomal abnormalities by sequencing circulating cell-free DNA from maternal plasma. Clin Chem 61(4):608–616

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Maternal-Fetal Medicine, Obstetrics and Gynecology, Harvard Medical School, Brigham and Women’s Hospital, 75 Francis St, Boston, MA, USA

    Stephanie H. Guseh

Authors
  1. Stephanie H. Guseh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephanie H. Guseh.

Ethics declarations

Conflict of interest

The corresponding author states that there is no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guseh, S.H. Noninvasive prenatal testing: from aneuploidy to single genes. Hum Genet 139, 1141–1148 (2020). https://doi.org/10.1007/s00439-019-02061-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-019-02061-1

Search

Navigation